Müller Christine, Gross Dietmar, Sarli Vasiliki, Gartner Michael, Giannis Athanassios, Bernhardt Günther, Buschauer Armin
Institute of Pharmacy, University of Regensburg, Universitätsstrasse 31, 93040, Regensburg, Germany.
Cancer Chemother Pharmacol. 2007 Feb;59(2):157-64. doi: 10.1007/s00280-006-0254-1. Epub 2006 May 16.
The inhibition of kinesin Eg5 by small molecules such as monastrol is currently evaluated as an approach to develop a novel class of antiproliferative drugs for the treatment of malignant tumours. Therefore, we studied the effects of the new monastrol analogues enastron, dimethylenastron and vasastrol VS-83 on the proliferation of human glioblastoma cells in the kinetic crystal violet assay. Compared to monastrol, the new cell cycle specific compounds showed an at least one order of magnitude higher anti proliferative activity against U-87 MG, U-118 MG, and U-373 MG glioblastoma cells. The compounds were neither inactivated by hydrolysis nor by binding to serum proteins. Moreover, we demonstrated the characteristic monoaster formation after incubation of cells with the new compounds by confocal laser scanning microscopy. We also showed that the arrangement of beta-actin and tubulin, vital components of the cyto-skeleton of mitotic and quiescent cells, were not affected by the new compounds. Due to the necessity of overcoming the blood-brain barrier in the treatment of brain tumours, we investigated if the new monastrol analogues are modulators or substrates of the p-glycoprotein (p-gp) 170 by a flow cytometric calcein-AM efflux assay. The tested compounds showed no modulating effects on the p-gp function. With respect to the treatment of primary and secondary CNS tumours, the results of our experiments suggest that the new monastrol analogues represent an interesting class of potential anticancer drugs, predicted to be less neurotoxic in comparison to classical tubulin inhibitors.
目前正在评估小分子（如单星孢菌素）对驱动蛋白Eg5的抑制作用，以此作为开发一类新型抗增殖药物用于治疗恶性肿瘤的一种方法。因此，我们在动态结晶紫试验中研究了新型单星孢菌素类似物恩那司特、二亚甲基单星孢菌素和血管星孢菌素VS-83对人胶质母细胞瘤细胞增殖的影响。与单星孢菌素相比，这些新的细胞周期特异性化合物对U-87 MG、U-118 MG和U-373 MG胶质母细胞瘤细胞显示出至少高一个数量级的抗增殖活性。这些化合物既不会因水解而失活，也不会因与血清蛋白结合而失活。此外，我们通过共聚焦激光扫描显微镜证明了细胞与新化合物孵育后形成了特征性的单星体。我们还表明，有丝分裂和静止细胞细胞骨架的重要组成部分β-肌动蛋白和微管蛋白的排列不受新化合物的影响。由于治疗脑肿瘤需要克服血脑屏障，我们通过流式细胞术钙黄绿素-AM外排试验研究了新型单星孢菌素类似物是否是P-糖蛋白（P-gp）170的调节剂或底物。测试的化合物对P-gp功能没有调节作用。关于原发性和继发性中枢神经系统肿瘤的治疗，我们实验结果表明，新型单星孢菌素类似物代表了一类有趣的潜在抗癌药物，预计与传统微管蛋白抑制剂相比神经毒性较小。
